1. Field of the Invention
The present invention relates to biodegradable poly(phosphoester) compositions that degrade in vivo into non-toxic residues, in particular those containing a cycloaliphatic structure in the polymer backbone. The compositions of the invention are particularly useful as flexible or flowable materials for localized, controlled drug delivery systems.
2. Description of the Prior Art
Biocompatible polymeric materials have been used extensively in therapeutic drug delivery and medical implant applications. If a medical implant is intended for use as a drug delivery or other controlled-release system, using a biodegradable polymeric carrier is one effective means to deliver the therapeutic agent locally and in a controlled fashion, see Langer et al., xe2x80x9cChemical and Physical Structures of Polymers as Carriers for Controlled Release of Bioactive Agentsxe2x80x9d, J. Macro. Science, Rev. Macro. Chem. Phys., C23(1), 61-126 (1983). As a result, less total drug is required, and toxic side effects can be minimized. Polymers have been used for some time as carriers of therapeutic agents to effect a localized and sustained release. See Leong et al., xe2x80x9cPolymeric Controlled Drug Deliveryxe2x80x9d, Advanced Drug Delivery Rev., 1:199-233 (1987); Langer, xe2x80x9cNew Methods of Drug Deliveryxe2x80x9d, Science, 249:1527-33 (1990) and Chien et al., Novel Drug Delivery Systems (1982). Such delivery systems offer the potential of enhanced therapeutic efficacy and reduced overall toxicity.
When a non-biodegradable polymer matrix is used, the steps leading to release of the therapeutic agent are water diffusion into the matrix, dissolution of the therapeutic agent, and diffusion of the therapeutic agent out through the channels of the matrix. As a consequence, the mean residence time of the therapeutic agent existing in the soluble state is normally longer for a non-biodegradable matrix than for a biodegradable matrix, for which passage through the channels of the matrix, while it may occur, is no longer required.
Since many pharmaceuticals have short half-lives, therapeutic agents can decompose or become inactivated within the non-biodegradable matrix before they are released. This issue is particularly significant for many bio-macromolecules, e.g., proteins and smaller polypeptides, since these molecules are generally hydrolytically unstable and have markedly low permeabilities through most polymer matrices. In non-biodegradable matrices, many bio-macromolecules even begin to aggregate and precipitate out of solution, blocking the very channels necessary for diffusion out of the carrier matrix.
These problems are alleviated somewhat by using a biodegradable rigid matrix that, in addition to some diffusional release, primarily allows the controlled release of the therapeutic agent by degradation of the solid polymer matrix. Examples of classes of synthetic polymers that have been studied as possible solid biodegradable materials include polyesters (Pitt et al., xe2x80x9cBiodegradable Drug Delivery Systems Based on Aliphatic Polyesters: Applications to Contraceptives and Narcotic Antagonistsxe2x80x9d, Controlled Release of Bioactive Materials, 19-44 (Richard Baker ed., 1980); poly(amino acids) and pseudo-poly(amino acids) (Pulapura et al. xe2x80x9cTrends in the Development of Bioresorbable Polymers for Medical Applicationsxe2x80x9d, J. Biomaterials Appl., 6:1, 216-50 (1992); polyurethanes (Bruin et al., xe2x80x9cBiodegradable Lysine Diisocyanate-based Poly(Glycolide-co-xcex5 Caprolactone)-Urethane Network in Artificial Skinxe2x80x9d, Biomaterials, 11:4, 291-95 (1990); polyorthoesters (Heller et al., xe2x80x9cRelease of Norethindrone from Poly(Ortho Esters)xe2x80x9d, Polymer Engineering Sci., 21:11, 727-31 (1981); and polyanhydrides (Leong et al., xe2x80x9cPolyanhydrides for Controlled Release of Bioactive Agentsxe2x80x9d, Biomaterials 7:5, 364-71 (1986).
Polymers having phosphate linkages, called poly(phosphates), poly(phosphonates) and poly(phosphites), are known. See Penczek et al., Handbook of Polymer Synthesis, Chapter 17: xe2x80x9cPhosphorus-Containing Polymersxe2x80x9d, (Hans R. Kricheldorf ed., 1992). The respective structures of these three classes of compounds, each having a different side chain connected to the phosphorus atom, are as follows: 
The versatility of these polymers comes from the versatility of the phosphorus atom, which is known for a multiplicity of reactions. Its bonding can involve the 3p orbitals or various 3s-3p hybrids; spd hybrids are also possible because of the accessible d orbitals. Thus, the physico-chemical properties of the poly(phosphoesters) can be readily changed by varying either the R or Rxe2x80x2 group. The biodegradability of the polymer is due primarily to the physiologically labile phosphoester bond in the backbone of the polymer. By manipulating the backbone or the side chain, a wide range of biodegradation rates are attainable.
An additional feature of poly(phosphoesters) is the availability of functional side groups. Because phosphorus can be pentavalent, drug molecules or other biologically active substances can be chemically linked to the polymer. For example, drugs with xe2x80x94O-carboxy groups may be coupled to the phosphorus via a phosphoester bond, which is hydrolyzable. See, Leong, U.S. Pat. Nos. 5,194,581 and 5,256,765. The P-O-C group in the backbone also lowers the glass transition temperature of the polymer and, importantly, confers solubility in common organic solvents, which is desirable for easy characterization and processing.
However, drug-delivery systems using most of the known biodegradable polymers, including those of phosphoesters, have been rigid materials. In such instances, the drug is incorporated into the polymer, and the mixture is shaped into a certain form, such as a cylinder, disc, or fiber for implantation.
However, proteins and other large biomolecules are still difficult to deliver from rigid biodegradables because these larger molecules are particularly unstable and are typically degraded along with the solid polymeric matrix carrier. More specifically, when a polymer begins to degrade following administration, a highly concentrated microenvironment is created from the breakdown by-products of the polymer as the polymer becomes ionized, protonated or hydrolyzed. Proteins are easily denatured or degraded under these conditions and then are useless for therapeutic purposes.
Further, in the process of preparing rigid drug delivery systems, biologically active substances such as proteins are commonly exposed to extreme stresses. Necessary manufacturing steps may include excessive exposure to heat, pH extremes, large amounts of organic solvents, cross-linking agents, freezing and drying. Following manufacture or preparation, the drug delivery systems must be stored for some extended period of time prior to administration, and little information is available on the subject of long term stability of proteins within solid biodegradable delivery systems.
Rigid polymers can be inserted into the body with a syringe or catheter in the form of small particles, such as microspheres or microcapsules. However, because they are still solid particles, they do not form the continuous and nearly homogeneous, monolithic matrix that is sometimes needed for preferred release profiles.
In addition, microspheres or microcapsules prepared from these polymers and containing biologically active substances to be released into the body are sometimes difficult to produce on a large scale. Most of the microencapsulation processes involve high temperature and contact with organic solvents, steps that tend to damage the bioactivity of proteins. Moreover, their storage often presents problems and, upon injection, their granular nature can cause blockages in injection devices and/or irritation of the soft tissues into which the small particles are injected.
Dunn et al., U.S. Pat. Nos. 5,278,201; 5,278,202; and 5,340,849, disclose a thermoplastic drug delivery system in which a solid, linear-chain, biodegradable polymer or copolymer is dissolved in a solvent to form a liquid solution. Once the polymer solution is placed into the body where there is sufficient water, the solvent dissipates or diffuses away from the polymer leaving it to coagulate or solidify into a solid substance. However, the system requires the presence of a solvent, and it is difficult to find an organic solvent that is sufficiently non-toxic for acceptable biocompatibility.
Thus, there exists a need for a composition and method for providing a flexible or flowable biodegradable composition that can be used in vivo to release a variety of different biologically active substances, including hydrophobic drugs and even large and bulky bio-macromolecules, such as therapeutically useful proteins, preferably without requiring the presence of significant amounts of organic solvent. There is also a continuing need for biodegradable polymer compositions that may provide controlled release in such a way that trauma to the surrounding soft tissues can be minimized.
Coover et al., U.S. Pat. No. 3,271,329, discloses organophosphorus polymers prepared from dialkyl or diaryl hydrogen phosphites and certain diol compounds, such as 1,4-cyclohexanedimethanol. See column 1, lines 24-31. Vandenberg et al., U.S. Pat. No. 3,655,585, discloses phosphorous polymers having at least one recurring unit having the formula: 
where R can be alkyl and Z can be alkylene such as cyclohexylene. See column 1, lines 28-55. Herwig et al., U.S. Pat. No. 3,875,263, discloses diphosphinic acid esters having a cyclic alkylene portion, e.g., 1,4-methylene-cyclohexane. See column 1, lines 18-37 and column 2, line 13.
However, all of these patents suggest that such compounds and polymeric compositions made from such compounds should be extruded or molded to form articles or spun into fibers (Coover et al.); used as additives for lubricating oils, gasoline, and synthetic resins or other polymers (Vandenberg et al. and Herwig et al.); or used as coating compounds (Herwig et al.). These compounds are known by those of skill in the art primarily as conferring high flame resistance and fire-proofing capabilities (Coover et al. and Herwig et al.) or increased stability to oxidation and heat and improved impact strength (Vandenberg et al.).
It has now been discovered that polymer compositions made with poly(cycloaliphatic phosphoester) compounds provide conveniently flexible or flowable carriers for even large and/or bulky bio-macromolecules, including hydrophobic drugs and even large and bulky bio-macromolecules, such as therapeutically useful proteins. The biodegradable polymer composition of the invention comprises a polymer having the recurring monomeric units shown in formula I: 
wherein:
each of R and Rxe2x80x2 is independently straight or branched aliphatic, either unsubstituted or substituted with one or more non-interfering substituents;
L is a divalent cycloaliphatic group;
Rxe2x80x3 is selected from the group consisting of H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy; and
n is 5 to 1,000
wherein the biodegradable polymer composition is biocompatible both before and upon biodegradation. In a particularly preferred embodiment, one or more of R, Rxe2x80x2 and Rxe2x80x3 is a biologically active substance in a form capable of being released in a physiological environment.
The invention also comprises a flexible article useful for implantation, injection, or otherwise placed totally or partially within the body, the article comprising a biodegradable, flowable or flexible polymer composition comprising a polymer having the recurring monomeric units shown in formula I where R, Rxe2x80x2, Rxe2x80x3, L and n are as defined above.
In yet another embodiment of the invention, a method is provided for the controlled release of a biologically active substance comprising the steps of:
(a) combining the biologically active substance with a biodegradable polymer having the recurring monomeric units shown in formula I: 
xe2x80x83where R, Rxe2x80x2, L, Rxe2x80x3 and n are as defined above, to form an implantable or injectable polymer composition; and
(b) placing the polymer composition formed in step (a) either partially or totally within the body at a preselected site in vivo, such that the polymer composition is in at least partial contact with a biological fluid.
Because the compositions of the invention are preferably viscous, flowable xe2x80x9cgel-likexe2x80x9d materials or flexible materials, they can be used to deliver a wide variety of drugs, for example, from hydrophobic drugs such as paclitaxel to large water-soluble macromolecules such as proteins. Even when not flowable, the compositions of the invention are still flexible and allow large proteins to, at least partially, diffuse through the matrix prior to the protein being degraded. The invention thus provides a delivery system that is both convenient for use and capable of delivering large bio-macromolecules in an effective manner.